1. Field of the Invention
The present invention relates to 4-(phenylamino)-[1,4]dioxano[2,3-g]quinazoline derivatives and a process for preparing the same, more specifically, to 4-(phenylamino)-[1,4]dioxano[2,3-g]quinazoline derivatives which inhibit the activity of tyrosine kinase of epidermal growth factor receptor (xe2x80x9cEGFRxe2x80x9d), and pharmaceutically acceptable salts, hydrates and solvates thereof, and a process for preparing the same.
2. Discussion of Related Technology
Experimental approaches have been conventionally made in the art, to explore and develop anticancer agents. However, as cellular metabolism becomes clear in the level of protein by employing the biochemical techniques, nowadays, they are being replaced by the methods based on reaction mechanism. Such a reaction mechanism-based development of anticancer agents has been realized by targeting a variety of biological phenomena such as cytotoxicity, antibody, hormone antagonist, signal transduction inhibition, cell cycle control, cell death, angiogenesis inhibition, invasion inhibition, etc.
Up to date, low-priced anticancer agents have been developed by chemical synthesis, and most of anticancer agents used for clinical purposes exhibit their anticancer activities by inhibiting DNA synthesis or biological function. However, the said agents have several problems such as attacking DNA of normal cells as well as cancer cells to cause side effects and toxicity, and inducing resistance.
Meanwhile, under a consideration that the phosphorylation of tyrosine by regulating the activities tyrosine kinase and tyrosine phosphatase is necessary for controlling the growth and differentiation of normal cells, extensive studies have been lately made on the development of novel anticancer agents which possess a selectivity between normal and cancer cells, by way of targating on signal transduction. Among kinases taken part in the signal transduction during cell growth, tyrosine kinase is classified largely into nontransmembrane and transmembrane growth factor receptor tyrosine kinases, where the transmembrane growth factor binds to a cell surface receptor to form a dimer in the cytosolic domain of the receptor which is subsequently activated and phosphorylated. Activation of such receptors causes a signal transduction cascade which regulates diverse cellular responses. This transmembrane growth factor receptor tyrosine kinase is known to participate in a variety of biological phenomena in vivo such as angiogenesis, atherosclerosis and cancer, thus, it is expected to be a key element in the development of anticancer agents which effectively treat cancer without harmful side-effects. However, since a number of tyrosine and serine/threonine kinases whose ATP binding sites are structurally similar are retarding the development of inhibitors specific to tyrosine kinase of transmembrane growth factor receptor, extensive studies are in progress to overcome the problems.
Recently, various 4-(phenylamino)quinazoline compounds have been proposed in the art, which includes PD153035 possessing selective and powerful inhibitory effect (IC50=29 pM) on tyrosine kinase of EGFR, known to be overexpressed in many human cancers, by way of competing with ATP (see: David W. Fry et al., Science, 265:1093-1095, 1994; Gordon W. Rewcastle et al., J. Med. Chem., 38:3482-3487, 1995; Alexander J. Bridges et al., J. Med. Chem., 39:267-276, 1996; WO 95/66226). However, it is difficult to evaluate in vivo pharmacological efficacy of the said compound using a tumor model because of its insolubility in water. Though ZD 1839(Iressa) to which a hydrophilic substituent is introduced was suggested in order to resolve the problem of insolubility, the said compound does not have a high solubility like the prior art compounds and shows a relatively low pharmacological efficacy.
Under the circumstances, there are strong reasons for exploring and developing 4-(phenylamino)quinazoline compounds which are highly soluble in water.
The present inventors have made an effort to develop novel 4-(phenylamino)quinazoline compounds possessing a high solubility in water, and finally found that 4-(phenylamino)-[1,4]dioxano[2,3-g]quinazoline derivatives effectively inhibit the activity of tyrosine kinase of EGFR and the growth of cancer cell, and exhibit a high solubility in water. A primary object of the present invention is, therefore, to provide 4-(phenylamino)-[1,4]dioxano[2,3-g]quinazoline derivatives which exhibit an inhibitory activity on tyrosine kinase, and pharmaceutically acceptable salts, hydrates and solvates thereof. The other object of the invention is to provide a process for preparing the same.
One aspect of the present invention provides a compound that has Formula I: 
or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: n is 1, 2 or 3, R1 is substituent group, may be identical or different when n is 2 or 3, and is selected from the group consisting of hydrogen, halogen, C1-6-alkyl, C3-6-cycloalkyl, hydroxy, C1-6-alkoxy, C3-6-cycloalkoxy, (aryl or heteroaryl)oxy, C1-6-thioalkoxy, C3-6-thiocycloalkoxy, thio(aryl or heteroaryl)oxy, nitro, amino, N-mono(C1-6)-alkylamino, N,N-di(C1-6)-alkylamino, formamido, amido, acetamido, hydroxyamino, C1-6-alkoxyamino, hydrazino, trifluoromethyl, trifluoromethoxy, alkenyl, alkynyl, aryl and heterocyclic; and R2 and R3 are substituent groups of xe2x80x94(CH2)mxe2x80x94R4 and may be identical or different, wherein m is 0 or 1, and wherein R4 is selected from the group consisting of hydrogen, halogen, C1-6-alkyl, C3-6-cycloalkyl, hydroxy, C1-6-alkoxy, C3-6-cycloalkoxy, C1-6-thioalkoxy, C3-6-thiocycloalkoxy, amino, mono(C1-6)-alkylamino, di(C1-6)-alkylamino, formamido, nitro, hydroxyamino, C1-6-alkoxyamino, hydrazino, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkyl(C1-6)-amido, N,N-dialkyl (C1-6)-amido, thioamido, N-monoalkyl(C1-6)-thioamido, N,N-dialkyl(C1-6)-thioamido, guanidino, ureido, C1-6-alkylsulfido, C1-6-alkylsulfonyl, trifluoromethyl, trifluoromethoxy, morpholino, 4-C1-6-alkylpiperidino, mono[hydroxy(C1-6)alkyl]amino, di[hydroxy(C1-6)alkyl]amino, mono[pyrrolidine(C1-6)alkyl]amino, and di[pyrrolidine(C1-6)alkyl]amino or xe2x80x94N(R5)(CHR6R7), wherein R5 is hydrogen or C1-6-alkyl, R6 is (CH2)nOH where n is an integer of 1 to 4, and R7 is selected from the group consisting of hydrogen, C1-5-alkyl, hydroxy(C1-5)-alkyl, thiohydroxy(C1-5)-alkyl, phenyl(C1-5)-alkyl, 4-hydroxyphenyl(C1-5)-alkyl and heteroallyl(C1-5)-alkyl.
In the above-discussed compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, the pharmaceutically acceptable salt comprises an inorganic acid salt, an organic acid salt or a sulfonic acid salt of the compound. The he inorganic acid salt is one or more selected from the group consisting of a hydrochloric acid salt, a hydrobromic acid salt, a hydroiodic acid salt, a sulfuric acid salt, a nitric acid salt and a phosphoric acid salt. The organic acid salt is one or more selected from the group consisting of an acetic acid salt, a succinic acid salt, a tartaric acid salt, a malic acid salt, a formic acid salt, a citric acid salt, a trichloroacetic acid salt, a trifluoroacetic acid salt, a gluconic acid salt, a lactic acid salt, a fumaric acid salt, a picric acid salt and a maleic acid salt. The sulfonic acid salt is one or more selected from the group consisting of a methane sulfonic acid salt, a benzene sulfonic acid salt, a p-toluene sulfonic acid salt and a naphthalene sulfonic acid salt. The above-discussed compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is selected from the group consisting of: (3-bromophenyl)-(7-methoxymethyl-[1,4]-dioxano[2,3-g]quinazolin-4-yl)-amine, (3,5-dichlorophenyl)-(7-methoxymethyl-[1,4]-dioxano[2,3-g]quinazolin-4-yl)-amine, (3,5-dimethylphenyl)-(7-methoxymethyl-[1,4]-dioxano[2,3-g]quinazolin-4-yl)-amine, (3,4,5-trifluorophenyl)-(7-methoxymethyl-[1,4]-dioxano[2,3-g]quinazolin-4-yl)-amine, (3-iodophenyl)-[7-(morpholin-4-yl-methyl)-[1,4]dioxano[2,3-g]quinazolin-4-yl]-amine, (3-bromophenyl)-[7-(morpholin-4-yl-methyl)-[1,4]dioxano[2,3-g]quinazolin-4-yl]-amine, (3-bromophenyl)-[7-(morpholin-4-yl-methyl)-[1,4]dioxano[2,3-g]quinazolin-4-yl]-amine hydrochloride, 2-[4-(3-bromophenylamine)-[1,4]dioxano[2,3-g]quinazolin-7-yl-methyl]-aminoethanol, and (3-bromophenyl)-[7-(4-methylpiperazin-1-yl) methyl-[1,4]dioxano[2,3-g] quinazolin-4-yl]-amine.
Another aspect of the present invention provides a process for preparing the above-discussed compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, the process comprising: providing a quinazoline derivative of Formula (II) and a substituted aniline of Formula (III): 
wherein Z is halogen, alkoxy, aryloxy or sulfonyloxy; mixing the quinazoline derivative and the substituted aniline in the presence of an organic solvent to provide a liquid mixture; and adding an acid to the liquid mixture, thereby forming the compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof In the mixing 1 equi. of the quinazoline derivative and 2 equi. of the substituted aniline are mixed together. The organic solvent is an inert organic solvent. The organic solvent is selected from the group consisting of an alkanol, an ester, a halogenated solvent, an ether, an aromatic solvent, N,N-dimethylformamide, and mixtures of the foregoing. The added acid is hydrochloric acid. The process further comprises maintaining the mixture after the addition of the acid at a temperature from about 20xc2x0 C. to about 80xc2x0 C.
Another aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutical carrier and the above-discussed compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
Still another aspect of the present invention provides a method of regulating activities of tyrosine kinase, comprising administering to a patient in need of such regulation a composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the above-discussed compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
A further aspect of the present invention provides a method of inhibiting cancer cell growth, comprising administering to a patient in need of such inhibition a composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the above-discussed compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
In the methods of regulating activities of tyrosine kinase and inhibiting cancer cell growth, the compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is selected from the group consisting of: (3-bromophenyl)-(7-methoxymethyl-[1,4]-dioxano[2,3-g]quinazolin-4-yl)-amine, (3,5-dichlorophenyl)-(7-methoxymethyl-[1,4]-dioxano[2,3-g]quinazolin-4-yl)-amine, (3,5-dimethylphenyl)-(7-methoxymethyl-[1,4]-dioxano[2,3-g]quinazolin-4-yl)-amine, (3,4,5-trifluorophenyl)-(7-methoxymethyl-[1,4]-dioxano[2,3-g]quinazolin-4-yl)-amine, (3-iodophenyl)-[7-(morpholin-4-yl-methyl)-[1,4]dioxano[2,3-g]quinazolin-4-yl]-amine, (3-bromophenyl)-[7-(morpholin-4-yl-methyl)-[1,4]dioxano[2,3-g]quinazolin-4-yl]-amine, (3-bromophenyl)-[7-(morpholin-4-yl-methyl)-[1,4]dioxano[2,3-g]quinazolin-4-yl]-amine hydrochloride, 2-[4-(3-bromophenylamine)-[1,4]dioxano[2,3-g]quinazolin-7-yl-methyl]-aminoethanol, and (3-bromophenyl)-[7-(4-methylpiperazin-1-yl) methyl-[1,4]dioxano[2,3-g]quinazolin-4-yl]-amine. In the method, the pharmaceutically acceptable salt comprises an inorganic acid salt, organic acid salt or sulfonic acid salt of the compound.